RESUMO
Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data.
RESUMO
Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.
RESUMO
Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.
RESUMO
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors.
Assuntos
Antidepressivos/farmacologia , Piperidinas/farmacologia , Propanóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Encéfalo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Masculino , Conformação Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Propanóis/administração & dosagem , Propanóis/química , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1-(1H-indol-4-yloxy)-3-(4-arylpiperidinyl)propan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. The fused aryl ring moiety contributed to the robust dual activities irrespective of the regiochemistry associated with its connectivity to the piperidine central ring.
Assuntos
Antidepressivos de Segunda Geração/síntese química , Propanóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Antidepressivos de Segunda Geração/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Propanóis/síntese química , Ligação Proteica , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinity at the 5-HT(1A) receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities.
Assuntos
Antidepressivos de Segunda Geração/química , Antidepressivos de Segunda Geração/farmacologia , Propanóis/química , Propanóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antidepressivos de Segunda Geração/síntese química , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Indóis/química , Indóis/farmacologia , Paroxetina/farmacologia , Propanóis/síntese química , Receptor 5-HT1A de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
Potent 5-HT1A/SSRIs at low nanomolar and subnanomolar concentrations were identified in a series of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols. Incorporation of an alpha-Me group in the piperidine ring with its specific stereochemistry enhanced binding affinity at the 5-HT reuptake site and in vitro 5-HT(1A) antagonist functional activity.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Propanóis/síntese química , Propanóis/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Indicadores e Reagentes , Paroxetina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. Modification of potential metabolic sites of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols further improved the in vitro binding affinities and functional antagonism.